Project Summary Both loud noise and conductive hearing loss can have long-term detrimental effects on hearing. The possible mechanisms have primarily been studied at high-order stages of the auditory pathway, but effects early in the pathway are relatively unknown, despite the likelihood that changes there could have consequences for all downstream processing. We found that sound-driven activity triggers a novel, slow adaptation mechanism that alters the properties of auditory nerve synapses, which are at the very start of the central auditory pathway. Within a week?s exposure to an augmented sound environment, auditory nerve synapses have reduced depression and expanded structure, as well as enhanced spiking in the postsynaptic bushy cells, which combine to enhance fidelity to synaptically-driven activity. By contrast, after one week of occluding the ear canal, auditory nerve synapses have increased depression and reduced size, with reduced spiking and fidelity in bushy cells. These changes are surprising, because it has long been thought that the early auditory pathway was unaffected by sensory experience, except under extreme, pathological conditions. This raises the possibility that this mechanism could be involved in disorders such as tinnitus and otitis media. Therefore, it is important to understand how this mechanism is normally triggered and what mechanisms underlie it. Aim #1 will examine the susceptibility of auditory nerve synapses to abnormal sound levels, in terms of age and duration of exposure. Aim #2 will use in vitro methods to uncover the mechanisms underlying the changes in synaptic function. Aim #3 will examine the functional consequences for synaptic fidelity, both in vitro and in vivo. Studying this mechanism will lead to new understanding of how synapses are normally regulated, as well as new treatments for disorders caused by abnormal activity, including tinnitus and otitis media.